Clinical symptoms of SARS‐CoV‐2 breakthrough infection during the Omicron period in relation to baseline immune status and booster vaccination—A prospective multicentre cohort of health professionals (SURPRISE study)

Abstract The effects of different types of pre‐existing immunity on the frequency of clinical symptoms caused by the SARS‐CoV‐2 breakthrough infection were prospectively assessed in healthcare workers during the Omicron period. Among 518 participants, hybrid immunity was associated with symptom reduction for dizziness, muscle or limb pain and headache as compared to vaccination only. Moreover, the frequencies of dizziness, cough and muscle or limb pain were lower in participants who had received a booster vaccine dose. Thus, hybrid immunity appeared to be superior in preventing specific symptoms during breakthrough infection compared to vaccination alone. A booster vaccine dose conferred additional symptom reduction.

For affiliations refer to page 4 has been shown to persist for up to 1 year during the alpha and delta pandemic waves, immunity against Omicron wanes after a few months in previously infected individuals. [1][2][3] Similarly, vaccineinduced protection against Omicron infection has been shown to diminish significantly over time, and receipt of a booster vaccine dose provides only a short-lived improvement. 2,4 As a result, the prevalence of hybrid immunity from vaccination in combination with prior or subsequent infection in the population increases progressively. 3 Concomitantly, recent data suggest that hybrid immunity from exposures to the SARS-CoV-2 virus and the vaccine confers the highest level of protection from Omicron infection. 1,2,[5][6][7] Compared with the high overall burden of disease, there is a scarcity of data assessing whether individual symptoms of breakthrough infections differ between subjects with pre-existing hybrid or vaccineinduced immunity and whether these symptoms are affected by booster vaccine doses. In this study, we aimed to assess the effects of these different types of pre-existing immunity on the frequency of clinical symptoms caused by the SARS-CoV-2 breakthrough infection during the Omicron period, with or without additional booster vaccine doses.

| Study design and population
The study was approved by the ethics committee of Eastern Switzerland (#2020-00502).
Our cohort study prospectively included health care workers (HCW) 16 years of age or older from seven healthcare networks located in northern and eastern Switzerland (SURPRISE study) since June 2020. From their inclusion until March 2022, participants were followed through questionnaires on SARS-CoV-2 infections and corresponding symptoms, vaccinations and periodic SARS-CoV-2 serology measurements. 8 Participants were asked to get tested for SARS-CoV-2 in case of compatible symptoms. SARS-CoV-2 was detected by polymerase chain reaction or rapid antigen test from nasopharyngeal swabs (NPS); self-reported NPS results were validated as previously described. 9 Anti-nucleocapsid (anti-N) and anti-spike (anti-S) antibodies were measured at baseline and in September 2021 using the Roche Elecsys (Roche Diagnostics, Rotkreuz, Switzerland) electro-chemiluminescence immunoassay 10

| Statistical analyses
Frequencies of individual COVID symptoms were described as percentages with 95% Wilson confidence intervals. We used multivariable logistic regression to assess the impact of immune status and booster vaccination on symptom frequencies. Models included a priori selected co-variables based on their importance in previous analyses, 12 that is, age, sex, body mass index >30 (yes/no), any T A B L E 1 Percentage of participants reporting each symptom (with 95% Wilson confidence intervals) for all breakthrough infections during the Omicron period and separately by group (vaccine-induced (V) vs. hybrid (H) immunity) and receipt of any booster vaccine at least 7 days before the positive swab. Symptoms are sorted by decreasing overall frequency.  Our study population consists of young, mostly healthy HCW in central Europe. Therefore, our results may not be generalizable to other populations, such as children and the elderly, and those in other socioeconomic systems. Furthermore, groups were imbalanced between vaccinated participants and those with hybrid immunity.
Another limitation is that SARS-CoV-2 testing was not mandatory, that the results of the NPS and symptoms associated with SARS-